Carbohydrates are digested through enzymic breakdown and absorption of simple sugars or through microbial fermentation and absorption of short chain volatile fatty acids. A condition known as lactic acidosis (D-lactic acidosis, fermentative acidosis or carbohydrate overload) is widely recognised in ruminants and horses. This condition is responsible for deaths in ruminant livestock feeding, and in horses is associated with the development of laminitis (Garner et al. 1987, Rowe et al. 1994) and abnormal behaviour (Johnson et al. 1998). Lactic acidosis can also lead to diarrhoea, infections in the hind gut and skin disorders. The pathogenesis of lactic acidosis is described as a good example of metabolic acidosis in which considerable amounts of lactic acid are absorbed through the wall of the gut (Blood et al. 1983). D-lactic acid is more slowly metabolised than L-lactic acid and therefore accumulates in the tissues where it causes severe D-lactic acidosis. These authors also suggest that endotoxins from gram-negative bacteria in the gut may play a role in the pathogenesis of lactic acidosis (Blood et al. 1983), as it is possible that these endotoxins may be absorbed as a result of severe structural damage to the gut epithelium which occurs during this condition (Krueger et al. 1986).
The present invention describes a new condition, described as acidic gut syndrome, which differs significantly from lactic acidosis in that it does not involve metabolic acidosis, resulting from acid absorption from the gastrointestinal tract, as a factor in its pathogenesis. Acidic gut syndrome depends entirely on acidity within the gut and the adverse toxic effects mediated through the direct effect of acid on the gut wall and through effects of acidity on microbes within the gut. Acidic gut syndrome has a range of secondary consequences which develop from the primary effects of acidity within the gut. These secondary effects occur both locally and systemically. Locally, the effects are through the action of acidity and bacterial endotoxins (produced for example, through the death of gram negative bacteria under acidic conditions) on the gut wall itself. Systemically the effects are considered to be mediated via the immune system and a range of cytokine and related factors. Furthermore, it is thought that the gut wall and gut associated lymphoid tissue play a role in acidic gut syndrome through mediating the effects of toxins or other factors, and releasing systemically active hormones and/or agents of the immune system.
There are a number of immune system diseases, of a chronic and/or acute nature, which are of unknown aetiology. The common factor appears to be the involvement of various cytokines and other mediators of the immune system. Because the aetiology of these immune-related conditions has not been understood they have generally been considered to be non-specific immune diseases. Examples of immune diseases considered in this category are forms of arthritis, including rheumatoid arthritis, forms of respiratory disease and susceptibility to respiratory problems such as asthma, reduced enzyme production by the pancreas leading to some forms of diabetes, damage to kidneys resulting in mineral imbalances and hypertension, effects on the brain which can lead to secondary hormone imbalances with respect to control of temperature regulation, reproductive functions and other key aspects of metabolic control. The effects mediated via the immune system (cytokine and possibly other activities) can also cause inflammation and damage membranes in organs and tissues remote from the sites of bacterial activity within the gut. Organs and tissues affected in this way can include the lung (which subsequently increases the risk of respiratory tract infection), the stomach (which increases the risk of ulcer development), the kidneys (affecting mineral retention and hypertension). There can also be local areas of non-specific inflammation such as can occur in the gut or around the teeth. These conditions are considered to result from a minor build up of acidity within the gut and the release of endotoxins associated with the death of gram negative bacteria as acidity increases and gram positive bacteria predominate.
The slight increases in levels of both acidity and endotoxin within the gut associated with acidic gut syndrome, effect the host via a subtle increase in the immune challenge. The barrier between the host and the gastrointestinal microflora is extremely important in preventing infection and/or toxaemia. The present invention describes how the immune challenge to the host from the gut is not constant and can be increased in response to levels of acid in the gut which have until now been considered within normal limits and of no biological consequence. Increased acidity and changes in gut bacteria, particularly in relation to endotoxin production, produces a challenge which may not necessarily lead to an immediately detectable disease condition or a dramatic immunological response in the animal. It does however pose a sufficient challenge to the immune system of the animal or human to cause measurable responses (for example raised levels of tumour necrosis factor (TNF), T-cells, monocytes, interferon and cytokines, including interleukin-1, -6 and -8). Because these changes to the immune system are small and in themselves do not cause symptoms or signs of disease they have not previously been linked to changes in the diet or digestive process. Slightly elevated levels of cytokines and or TNF tend to be transitory and have previously been regarded as normal variation between individuals or non-specific immune conditions, and for these reasons have not been studied systematically with a view to determining the importance of diet and microbial activity within the gut. There has therefore been no previous suggestion that diet, fermentation within the gut, and subsequent acid accumulation and endotoxin production in the gut (acidic gut syndrome), are the primary causes of serious chronic and/or sporadic disease conditions of previously unknown origin.
There is a dense and diverse population of bacteria which inhabit the gastro-intestinal tract of man and animals. The concentration of these bacteria occurs naturally in those parts of the tract where the conditions of pH are close to neutral (around pH 6.5 to 7.5) and where fermentable substrate is available for fermentation. The bacteria in the gut poses a potential risk to the animal in terms of infection from the gut or through the absorption of microbial toxins.
The medical and nutritional literature contains information on various approaches used to manage the microbial population within the gut of humans. Two of these are summarised below.
1. The creation of a population of lactic acid producing bacteria in the gut through inoculation with probiotics such as cultures of Lactobacilli and other lactic acid producing bacteria, in the form of yoghurt cultures or specifically cultured bacteria preparations. The hypothesis behind this practice is that the lactic acid production may exclude other, more pathogenic, bacteria from the gut.
2. Consumption of increased amounts of soluble fibre which consists of indigestible (but fermentable) sources of starch (resistant starch) and oligosaccharides in order to provide substrates for fermentation in the hind gut. The aim of this practice is to increase the production of butyric acid, which has been shown, in vitro, to enhance the metabolism of the gut epithelium and reduce the risk of colonic cancer.
It is clear that these practices, now widely recommended by dietitians and medical practitioners, are likely to increase the amount of fermentable acid production and, specifically, the amount of lactic acid and are therefore likely to promote acidic gut syndrome.
The present invention describes how the elevated activity of the immune system, as a result of acidic gut syndrome, is sufficient to initiate, or predispose, the host to a range of secondary conditions including immune diseases, inflammation, infection and damage to membranes, by cytokine, or other immune system activity, and provides a method for the treatment or prophylaxis of acidic gut syndrome.